Edith M. Schneider Gasser

Data on sleep and respiratory patterns among adolescents residing at very high altitude (> 3500 m) remain scarce, and altitude‐related physiological differences may influence these parameters. Studying adolescents at different very high altitudes is crucial, as subtle environmental variations could affect sleep‐related oxygenation and respiratory function. This study aimed to characterise sleep‐related oxygenation and respiratory parameters in healthy adolescents native to two distinct very high‐altitude environments. Overnight sleep polygraphy was performed in 163 healthy adolescents aged 13.5 to < 18 years living in La Paz (3620 m) and El Alto (4060 m), Bolivia. Mean nocturnal oxygen saturation, oxygen desaturation index, and apnea–hypopnea index were assessed alongside subjective sleep quality, morning blood pressure, heart rate, haemoglobin concentration, and Epworth Sleepiness Scale scores. Adolescents at 4060 m had significantly lower mean nocturnal oxygen saturation (84.8% ± 2.2%) compared with those at 3620 m (87.8% ± 1.8%), and a higher oxygen desaturation index (21.2 ± 8.5/h vs. 17.1 ± 9.0/h). The apnea‐hypopnea index did not differ significantly between altitudes (6.2 ± 4.8/h vs. 5.6 ± 4.6/h). At 3620 m, females showed lower oxygen desaturation and apnea‐hypopnea indices compared with males. Despite the more pronounced nocturnal hypoxemia at 4060 m, haemoglobin concentration did not increase, suggesting limited haematological compensation. Subjective sleep quality, blood pressure, and heart rate were similar between both altitude groups. Healthy adolescents living chronically at very high altitude exhibit altitude‐dependent reductions in nocturnal oxygenation and increased desaturation frequency, without evidence of sleep‐disordered breathing. These findings underscore the need for altitude‐specific normative values to support accurate interpretation of sleep studies in high‐altitude populations.

Species living at high altitude (HA) often exhibit optimized oxygen utilization at adulthood; however, the plasticity of metabolic pathways during postnatal development remains unclear. Because mice, but not rats, are commonly found at HA, we investigated mitochondrial oxygen consumption rates (OCR) in the cerebral cortex of both species across postnatal development and at adulthood at sea level (SL; Quebec, Canada) under normoxia or hypoxia (13.5% O2), and at HA (La Paz, Bolivia, 3600 m) after 50 generations of residency. At postnatal day (P)7, P14 and P21 and in adults (P60–90), fresh tissue samples were used to assess mitochondrial OCR under states of proton LEAK (OCRLEAK(N)) and oxidative phosphorylation (OXPHOS) using substrates for complex I (N pathway – OCRN), complex II (S pathway – OCRS) and complexes I+II (NS pathways – OCRNS). Our results showed: (1) at HA, rats exhibit higher OCR at P7, P14 and adulthood compared with their SL counterparts, and (2) HA residency induces a shift from the N pathway to the S pathway at all ages in mice. Finally, these responses were absent in SL animals exposed to postnatal hypoxia, highlighting the importance of studying HA-living species. These findings emphasize key metabolic shifts, with implications for understanding responses to hypoxia in species showing divergent success at HA.

Prenatal exposure to infections is a risk factor for neurodevelopmental disorders in offspring, and alterations in mitochondrial function are discussed as a potential underlying factor. Here, using a mouse model of viral-like maternal immune activation (MIA) based on poly(I:C) (POL) treatment at gestational day (GD) 12, we show that adult offspring exhibit behavioral deficits, such as reduced levels of social interaction. In addition, we found increased nicotinamidadenindinucleotid (NADH)- and succinate-linked mitochondrial respiration and maximal electron transfer capacity in the prefrontal cortex (PFC) and in the amygdala (AMY) of males and females. The increase in respiratory capacity resulted from an increase in mitochondrial mass in neurons (as measured by complex IV activity and transcript expression), presumably to compensate for a reduction in mitochondrion-specific respiration. Moreover, in the PFC of control (CON) male offspring a higher excess capacity compared to females was observed, which was significantly reduced in the POL-exposed male offspring, and, along with a higher leak respiration, resulted in a lower mitochondrial coupling efficiency. Transcript expression of the uncoupling proteins (UCP4 and UCP5) showed a reduction in the PFC of POL male mice, suggesting mitochondrial dysfunction. In addition, in the PFC of CON females, a higher expression of the antioxidant enzyme superoxide dismutase (SOD1) was observed, suggesting a higher antioxidant capacity as compared to males. Finally, transcripts analysis of genes involved in mitochondrial biogenesis and dynamics showed reduced expression of fission/fusion transcripts in PFC of POL offspring of both sexes. In conclusion, we show that MIA causes alterations in neuronal mitochondrial function and mass in the PFC and AMY of adult offspring with some effects differing between males and females.

Prenatal exposure to infections is a risk factor for neurodevelopmental disorders in offspring, and alterations in mitochondrial function are discussed as a potential underlying factor. Here, using a mouse model of viral-like maternal immune activation based on poly(I:C) (POL) treatment at gestational day (GD) 12, we show that adult offspring exhibit behavioral deficits, such as reduced levels of social interaction. In addition, we found increased NADH- and succinate-linked mitochondrial respiration and maximal electron transfer capacity in the prefrontal cortex (PFC) and in the amygdala (AMY) of males and females. The increase in respiratory capacity resulted from an increase in mitochondrial mass in neurons (as measured by complex IV activity and transcript expression), presumably to compensate for a reduction in mitochondrion-specific respiration. Moreover, in the PFC of control (CON) male offspring a higher excess capacity compared to females was observed, which was significantly reduced in the POL-exposed male offspring, and, along with a higher leak respiration, resulted in a lower mitochondrial coupling efficiency. Transcript expression of the uncoupling proteins (UCP4 and UCP5) showed a reduction in the PFC of POL male mice, suggesting mitochondrial dysfunction. In addition, in the PFC of CON females, a higher expression of the antioxidant enzyme superoxide dismutase (SOD1) was observed, suggesting a higher antioxidant capacity as compared to males. Finally, transcripts analysis of genes involved in mitochondrial biogenesis and dynamics showed reduced expression of fission/fusion transcripts in PFC of POL offspring of both sexes. In conclusion, we show that MIA causes alterations in neuronal mitochondrial function and mass in the PFC and AMY of adult offspring with some effects differing between males and females.

Myelination is a process tightly regulated by a variety of neurotrophic factors. Here, we show—by analyzing two transgenic mouse lines, one overexpressing EPO selectively in the brain Tg21(PDGFB-rhEPO) and another with targeted removal of EPO receptors (EPORs) from oligodendrocyte progenitor cells (OPC)s (Sox10-cre;EpoRfx/fx mice)—a key function for EPO in regulating developmental brain myelination. Overexpression of EPO resulted in faster postnatal brain growth and myelination, an increased number of myelinating oligodendrocytes, faster axonal myelin ensheathment, and improved motor coordination. Conversely, targeted ablation of EPORs from OPCs reduced the number of mature oligodendrocytes and impaired motor coordination during the second postnatal week. Furthermore, we found that EPORs are transiently expressed in the subventricular zone (SVZ) during the second postnatal week and EPO increases the postnatal expression of essential oligodendrocyte pro-differentiation and pro-maturation (Nkx6.2 and Myrf) transcripts, and the Nfatc2/calcineurin pathway. In contrast, ablation of EPORs from OPCs inactivated the Erk1/2 pathway and reduced the postnatal expression of the transcripts. Our results reveal developmental time windows in which EPO therapies could be highly effective for stimulating oligodendrocyte maturation and myelination.

Myelination is a process that is tightly regulated by a variety of neurotrophic factors. Here, we show - by analyzing two transgenic mouse lines, one overexpressing EPO selectively in the brain Tg21(PDGFB-rhEPO), and another with targeted removal of EPO receptors (EPORs) from oligodendrocyte progenitor cells (OPC)s (Sox10-cre;EPOR^fl/flmice) – a key function for EPO in regulating developmental brain myelination. Overexpression of EPO resulted in faster postnatal brain growth and myelination, an increased number of myelinating oligodendrocytes, faster axonal myelin ensheathment, and improved motor coordination. Inversely, targeted ablation of EPORs from OPCs reduced the number of mature oligodendrocytes and impaired motor coordination during the second postnatal week. Further, we found that EPORs are transiently expressed in the subventricular zone (SVZ) during the second postnatal week, and they stimulate the Erk1/2 pathway as well as the expression of essential oligodendrocyte pro-differentiation and pro-maturation transcripts (Nkx6.2 and Myrf), and the Nfatc2/calcineurin pathway. Our results reveal developmental time windows in which EPORs are expressed when therapies could be highly effective for stimulating oligodendrocyte maturation and myelination.

The brain requires over one-fifth of the total body oxygen demand for normal functioning. At high altitude (HA), the lower atmospheric oxygen pressure inevitably challenges the brain, affecting voluntary spatial attention, cognitive processing, and attention speed after short-term, long-term, or lifespan exposure. Molecular responses to HA are controlled mainly by hypoxia-inducible factors. This review aims to summarize the cellular, metabolic, and functional alterations in the brain at HA with a focus on the role of hypoxia-inducible factors in controlling the hypoxic ventilatory response, neuronal survival, metabolism, neurogenesis, synaptogenesis, and plasticity.

Editorial: Erythropoietin and Its Analogues as Therapeutics for Neurological Diseases

Erythropoietin (EPO) improves neuronal mitochondrial function and cognition in adults after brain injury and in those afflicted by psychiatric disorders. However, the influence of EPO on mitochondria and cognition during development remains unexplored. We previously observed that EPO stimulates hippocampal-specific neuronal maturation and synaptogenesis early in postnatal development in mice. Here we show that EPO promotes mitochondrial respiration in developing postnatal hippocampus by increasing mitochondrial content and enhancing cellular respiratory potential. Ultrastructurally, mitochondria profiles and total vesicle content were greater in presynaptic axon terminals, suggesting that EPO enhances oxidative metabolism and synaptic transmission capabilities. Behavioural tests of hippocampus-dependent memory at early adulthood, showed that EPO improves spatial and short-term memory. Collectively, we identify a role for EPO in the murine postnatal hippocampus by promoting mitochondrial function throughout early postnatal development, which corresponds to enhanced cognition by early adulthood.